Identification and Preclinical Evaluation of New Brain Tumor Therapies

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DESCRIPTION (provided by applicant): The optic pathway glioma (OPG), a brain tumor composed of neoplastic NF1-deficient astrocytes, is the second most common tumor in individuals affected with the neurofibromatosis 1 (NF1) tumor predisposition syndrome. While these tumors are often regarded as "benign" brain tumors, their continued growth can result in loss of vision and hypothalamic dysfunction (early puberty). Currently, therapy for NF1 OPG is based on the use of compounds that have been successfully employed to treat other low-grade brain tumors, including carboplatin and temozolamide. Unfortunately, tumor progression occurs in one-third of children, necessitating additional therapy. We have recently developed and extensively characterized a mouse model of NF1-associated OPG, in which low-grade optic nerve and chiasm tumors develop by 2 months of age. In an effort to provide an efficient approach for the identification, initial validation, and in vivo preclinical evaluation of new anti-cancer compounds suitable for the treatment of patients with NF1-associated brain tumors, we have initiated a multidisciplinary therapeutic discovery and preclinical chemotherapy testing program. Using this team-based approach, we have identified two novel drug candidates for NF1 -associated brain tumor therapy, rapamycin and AMD3100, which inhibit Nf1-/- astrocyte growth in vitro. In this project, we propose to employ the Nf1 mouse OPG model as a preclinical platform for anti-tumor drug evaluation. First, we plan to characterize the Nf1 mouse OPG model with respect to visual physiology and radiographic features as a function of tumor growth and in response to conventional human NF1 -associated brain tumor therapy. Second, we plan to evaluate rapamycin and AMD3100 as potential therapies for NF1-associated brain tumors. With the unique combination of a multidisciplinary team of scientists and clinicians focused on NF1-associated OPG therapeutics and the availability of a well-characterized mouse model for NF1- associated OPG, we are uniquely positioned to establish such a translational research program.